Impaired mTOR/S6 signaling pathway contributes to neurodegeneration in early postnatal Nbs1‐deficient mouse cerebral cortex

Abstract

Nijmegen breakage syndrome (NBS) is a genomic instability disease caused by hypomorphic mutations of NBS1 gene encoding Nbs1 protein. The Nbs1 protein is a component of the Mre11/Rad50/Nbs1 (MRN) complex that acts as a DNA double‐strand break sensor and functions in response to DNA damage. We have generated a mouse model (termed as NbnCNS‐del mice) by inactivating Nbn gene in the mouse central nervous system (CNS) with nestin‐Cre system. Our previous study has indicated that the neurons in the cerebral cortex, hippocampus and thalamus of NbnCNS‐del mice displayed neurodegeneration changes that consist of size reduction, numerical decreasing and disorganization. However, the molecular mechanisms of the phenotype remain unknown. In the present study, we report that in cerebral cortical neurons, Nbs1 deficiency affects glial cell function, for the reduced expression level of nerve growth factor (NGF) mRNA and protein. In turn, altered glial cell function results in the down‐regulation of neuronal mTOR and S6 ribosomal protein expression in postnatal NbnCNS‐del mice. This result demonstrates that the interplay between neuron and glia contributes to the neurodegeneration, and implies an important role of DNA damage response in neuron.This work is supported in part by National Novel Drug Development Fund (2009ZX09303‐008), and by 111 project (B08007).